Bacterial infections are often accompanied by inflammation of the infected tissues. For example, during pathogenesis of periodontal disease, it is generally accepted that while bacteria cause tissue destruction via release of virulence factors, a major role has been proposed for the host itself. The current concept is that bacteria produce inflammogens including lipopolysaccharides, which trigger mononuclear host cells resulting in bone and connective tissue destruction. These destructive mechanisms include periodontal triggering of macrophage and fibroblast collagenase which degrades tissue collagen, and stimulation of the production, by mononuclear cells, of interleukin-2 and other cytokines which stimulate local bone resorption.
While antibiotics have been successfully used to treat periodontitis, recent studies show that anti-inflammatory agents also reduce chronic destructive periodontitis (Williams et al. 1989, J. Periodontology 60:485-490; Reddy et al. 1993, J. Clinical Periodontology 20:635-640). Most of the anti-inflammatory approaches used so far utilize the systemic non-steroidal anti-inflammatory flurboprofen which has a risk of adverse systemic effects such as gastric ulcers. Furthermore, most anti-inflammatory agents that have been proposed for topical application are designed for systemic use and hence have significant systemic absorption potential, especially when used over long periods of time.
One group of anti-inflammatory compounds disclosed previously includes salicylanilides. U.S. Pat. No. 4,742,083 (Ritchey) discloses anti-inflammatory uses of substituted salicylanilides of the general formula: ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 are defined hydrocarbon attachments and Y is --OH or a phenolic ester group. These salicylanilide derivatives have also been shown to be effective anti-plaque agents (Coburn et al. U.S. Pat. Nos. 4,287,191; 4,358,443). The most effective of these compounds is defined by the formula: ##STR3## where n=6, X is ##STR4## and --R.sub.3 is a meta-trifluoromethylphenyl group (AMCF3-8 in U.S. Pat. No. 4,742,083). This compound has a pKa of 6.1 rendering it relatively insoluble in aqueous solutions at neutral pH.
Another anti-inflammatory compound disclosed previously for both systemic and topical use is 2',4,4'-trichloro-2-hydroxy-diphenyl-ether, also known as Triclosan.TM. (Van Der Ouderaa et al. U.S. Pat. No. 5,240,696).
Thus, currently available topical anti-inflammatory compounds have either high systemic absorption or low solubility in formulations typically used in topical applications. A need therefore exists for effective anti-inflammatory compounds that are lipophilic thereby reducing the risk of systemic absorption, and are also easily solubilized in formulations suitable for topical application.